HLA identical siblings of an insulin dependent diabetic have a high risk of develo]ping diabetes whereas, in those siblings that share neither haplotype with the diabetic, the risk is only slightly greater than in the general population. In preliminary studies, we have evaluated insuling secretion in ten HLA identical siblings and five siblings sharing neither haplotype with the diabetic. The insulin response to maximal stimulating doses of glucose was markedly exaggerated in the haplo-identical siblings but completely normal in those that shared neither haplotype. Since increased insulin secretion in animals is associated with an increased risk of developing diabetes when exposed to certain viruses or drugs toxic to beta cells, we have hypothesized that the increased beta cell activity in the siblings HLA identical to the diabetic may increase their risk of damage by environmental factors and thereby be part of the mechanism underlying their high risk state. In this application, we describe our proposed plan to confirm and validate our preliminary findings in a larger number of subjects and determine the mechanism underlying this hyperinsulinemia. Is it due to a primary beta cell abnormality and/or is it due to insulin resistance?